This invention relates to novel, aromatic compounds and pharmaceutically-acceptable salts thereof which possess useful pharmacological properties. More particularly the compounds of the invention are antagonists of the pain enhancing effects of E-type prostaglandins. The invention also relates to processes for the manufacture of the aromatic compounds and pharmaceutically-acceptable salts thereof; to novel pharmaceutical compositions containing them; and to use of the compounds in pain relief.
The compounds of the invention are useful in the treatment of pain such as the pain associated with joint conditions (such as rheumatoid arthritis and osteoarthritis), postoperative pain, postpartum pain, the pain associated with dental conditions (such as dental caries and gingivitis), the pain associated with bums (including sunburn), the treatment of bone disorders (such as osteoporosis, hypercalcaemia of malignancy and Paget""s disease), the pain associated with sports injuries and sprains and all other painful conditions in which E-type prostaglandins wholly or in part play a pathophysiological role.
Non-steroidal anti-inflammatory drugs (NSAIDS) and opiates are the main classes of drugs in pain relief. However both possess undesirable side effects. NSAIDS are known to cause gastrointestinal irritation and opiates are known to be addictive.
We have now found a class of compounds structurally different to NSAIDS and opiates, and useful in relief of pain.
The compounds of the invention may also possess anti-inflammatory, anti-pyretic and anti-diarrheal properties and be effective in other conditions in which prostaglandin E2 (PGE2) wholly or in part plays a pathophysiological role.
According to the invention there is provided a compound of the formula I: 
wherein:
A is an optionally substituted: phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl or thiadiazolyl having at least two adjacent ring carbon atoms; provided that the xe2x80x94CH(R3)N(R2)Bxe2x80x94R1 and xe2x80x94OR4 groups are positioned in a 1,2 relationship to one another on ring carbon atoms and the ring atom positioned ortho to the OR4 linking group (and therefore in the 3-position relative to the xe2x80x94CHR3NR2-linking group) is not substituted;
B is an optionally substituted: phenyl, pyridyl, thiazolyl, oxazolyl, thienyl, thiadiazolyl, imidazolyl, pyrazinyl, pyridazinyl or pyrimidyl;
R1 is positioned on ring B in a 1,3 or 1,4 relationship with the xe2x80x94CH(R3)N(R2)-linking group and is carboxy, carboxyC1-3alkyl, tetrazolyl, tetrazolylC1-3alkyl, tetronic acid, hydroxamic acid, sulphonic acid, or R1 is of the formula xe2x80x94CONRaRa1 wherein Ra is hydrogen or C1-6alkyl and Ra1 is hydrogen, C1-6alkyl (optionally substituted by halo, amino, C1-4alkylamino, di-C1-4alylamino, hydroxy, nitro, cyano, trifluoromethyl, C1-4alkoxy or C1-4alkoxycarbonyl), C2-6alkenyl (provided the double bond in not in the 1-position), C2-6alkynyl (provided the triple bond is not in the 1-position), carboxyphenyl, 5- or 6-membered heterocyclylC1-3alkyl, 5- or 6-membered heteroarylC3alkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl or Ra and Ra1 together with the amide nitrogen to which they are attached (NRaRa1) form an amino acid residue or ester thereof, or R1 is of the formula xe2x80x94CONHSO2Rb wherein Rb is C1-6alkyl (optionally substituted by halo, hydroxy, nitro, cyano, trifluoromethyl, C1-4alkoxy, amino, C1-4alkylamino, di-C1-4alkylamino or C1-4alkoxycarbonyl), C2-6alkenyl (provided the double bond is not in the 1-position), C2-6alkynyl (provided the triple bond is not in the 1-position), 5- or 6-membered heterocyclylC1-3alkyl, 5- or 6-membered heteroarylC3alkyl, phenylC1-3alkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl or phenyl; wherein any heterocyclyl or heteroaryl group in Ra1 is optionally substituted by halo, hydroxy, nitro, cyano, trifluoromethyl, C1-4alkoxy or C1-4alkoxycarbonyl and any phenyl, heterocyclyl or heteroaryl group in Rb is optionally substituted by halo, trifluoromethyl, nitro, hydroxy, amino, cyano, C1-6alkoxy, C1-6alkylS(O)p-(p is 0, 1 or 2), C1-6alkyl carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C2-6alkenyl, C2-6alkynyl, C1-4alkoxycarbonylamino, C1-4alkanoylamino, C1-4alkanoyl(Nxe2x80x94C1-4alkyl)amino, C1-4alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C1-4alkylaminosulphonyl, di(C1-4alkyl)aminosulphonyl, C1-4alkoxycarbonyl, C1-4alkanoyloxy, C1-6alkanoyl, formylC1-4alkyl, hydroxyiminoC1-6alkyl, C1-4alkoxyiminoC1-6alkyl or C1-6alkylcarbamoylamino; or R1 is of the formula xe2x80x94SO2N(Rc)Rc1 wherein Rc is hydrogen or C1-4alkyl and Rc1 is hydrogen or C1-4alkyl; or R1 is of the formula (IA), (IB) or (IC): 
wherein
X is CH or nitrogen, Y is oxygen or sulphur, Yxe2x80x2 is oxygen or NRd and Z is CH2, NRd or oxygen provided that there is no more than one ring oxygen and there are at least two ring heteroatoms and wherein Rd is hydrogen or C1-4alkyl;
R2 is hydrogen, C1-6alkyl, optionally substituted by hydroxy, cyano or trifluoromethyl, C2-6alkenyl (provided the double bond is not in the 1-position), C2-6alkynyl (provided the triple bond is not in the 1-position), phenylC1-3alkyl or pyridylC1-3alkyl;
R3 is hydrogen, methyl or ethyl;
R4 is optionally substituted: C1-6alkyl, C3-7cycloalkylC1 3alkyl or C3-7cycloalkyl; and N-oxides of xe2x80x94NR2 where chemically possible; and S-oxides of sulphur containing rings where chemically possible;
and pharmaceutically acceptable salts and in vivo hydrolysable esters and amides thereof; excluding 2-[2-methoxybenzylamino]pyridine-5-carboxylic acid, 4-[2-methoxybenzylamino]benzoic acid, 5-[2,3-dimethoxybenzylamino]-2-chloro-3-aminosulphonylbenzoic acid and 5-[2,5-dimethoxybenzylamino]-2-hydroxybenzoic acid.
A 5- or 6-membered heteroaryl ring system is a monocyclic aryl ring system having 5 or 6 ring atoms wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen and sulphur.
A 5- or 6-membered saturated or partially saturated heterocyclic ring is a ring system having 5 or 6 ring atoms wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulphur.
Particular 5- or 6-membered monocyclic heteroaryl rings include pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, thienyl, furyl and oxazolyl.
Particular 5- or 6-membered saturated or partially saturated heterocyclic ring systems include pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.
Particular substituents for ring carbon atoms in A (heterocyclyl and heteroaryl rings) include halo, trifluoromethyl, nitro, hydroxy, amino, C1-4alkylamino, diC1-4alkylamino, cyano, C1-6alkoxy, C1-6alkylS(O)p- (p is 0, 1 or 2), C1-6alkyl (optionally substituted by hydroxy, amino, halo, nitro or cyano), CF3S(O)p-(p=0, or 2), carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C2-6alkenyl, C2-6alkynyl, C1-4alkoxycarbonylamino, C1-4alkanoylamino, C1-4alkanoyl(Nxe2x80x94C1-4alkyl)amino, C1-4alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C1-4alkylaminosulphonyl, C1-4alkanoylaminosulphonyl, di(C1-4alkyl)aminosulphonyl, C1-4alkoxycarbonyl, C1-4alkanoyloxy, C1-6alkanoyl, formylC1-4alkyl, trifluoroC1-3alkylsulphonyl, hydroxyiminoC1-6alkyl, C1-4alkoxyiminoC1-6alkyl and C1-6alkylcarbamoylamino.
Where a ring nitrogen atom in A can be substituted without becoming quaternized, it is unsubstituted or substituted by C1-4alkyl.
Particular substituents for ring carbon atoms in B include halo, trifluoromethyl, nitro, hydroxy, C1-6alkoxy, C1-6alkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, cyano, C1-6alkyl S(O)p-(p is 0, 1 or 2), carbamoyl, C1-4alkylcarbamoyl and di(C1-4alkyl)carbamoyl.
Where a ring nitrogen atom in B can be substituted without becoming quaternized, it is unsubstituted or substituted by C1-4alkyl.
The term alkyl when used herein includes straight chain and branched chain substituents for example methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl and functional groups on alkyl chains may be anywhere on the chain, for example hydroxyiminoC1-6alkyl includes 1-(hydroxyimino)propyl and 2-(hydroxyimino)propyl.
C1-6alkyl substituted by halo includes trifluoromethyl.
Amino acid residues formed from Ra and Ra1 together with the nitrogen to which they are attached include residues (xe2x80x94NHCH(R)COOH) derived from naturally-occurring and non-naturally-occurring amino acids. Examples of, suitable amino acids include glycine, alanine, serine, threonine, phenylalanine, glutamic acid, tyrosine, lysine and dimethylglycine.
Suitable ring systems of the formula (IA), (IB), or (IC) include 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 3-oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl, 3-thioxo-2,3-dihydro- 1,2,4-oxadiazol-5-yl, 5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl, 5-oxo-4,5-dihydro-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 3-hydroxy-2-methylpyrazol-5-yl, 3-oxo-2,3-dihydroisoxazol-5-yl, 5-oxo-1,5-dihydroisoxazol-3-yl and 5-oxo-2,3-dihydropyrazol-3-yl.
Examples of C1-6alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl; examples of carboxyC1-3alkyl are carboxymethyl, 2-carboxyethyl, 1-carboxyethyl and 3-carboxypropyl; examples of C1-6alkoxycarbonylC1-3alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl; examples of tetrazolylC1-3alkyl are tetrazolylmethyl and 2-tetrazolylethyl; examples of C1-4alkoxy are methoxy, ethoxy, propoxy and isopropoxy; examples of C2-6alkenyl are vinyl and allyl; examples of C2-6alkynyl are ethynyl and propynyl; examples of C1-4alkanoyl are formyl, acetyl, propionyl and butyryl; examples of halo are fluoro, chloro, bromo and iodo; examples of C1-4alkylamino are methylamino, ethylamino, propylamino and isopropylamino; examples of di(C1-4alkyl)amine are dimethylamino, diethylamino and ethylmethylamino; examples of C1-6alkylS(O)p- are methylthio, methylsulphinyl and methylsulphonyl; examples of C1-4alkylcarbamoyl are methylcarbamoyl and ethylcarbamoyl; examples of di(C1-4alkyl)carbamoyl are dimethylcarbamoyl, diethylcarbamoyl and ethylmethylcarbamoyl; examples of C1-6alkyl are methyl, ethyl, propyl and isopropyl; examples of C1-4alkoxycarbonylamino are methoxycarbonylamino and ethoxycarbonylamino; examples of C1-4alkanoylamino are acetamido and propionamido; examples of C1-4alkanoyl(Nxe2x80x94C1-4alkyl)amino are N-methylacetamido and N-methylpropionamido; examples of C1-4alkanesulphonamido are methanesulphonamido and ethanesulphonamido; examples of C1-4alkylaminosulphonyl are methylaminosulphonyl and ethylaminosulphonyl; examples of di(C1-4alkyl)aminosulphonyl are dimethylaminosulphonyl, diethylaminosulphonyl and ethylmethylaminosulphonyl; examples of C1-4alkanoyloxy are acetyloxy and propionyloxy; examples of formylC1-4alkyl are formylmethyl and 2-formylethyl; examples of hydroxyiminoC1-6alkyl are hydroxyiminomethyl and 2-(hydroxyimino)ethyl; and examples of C1-4alkoxyiminoC1-6alkyl are methoxyiminomethyl, ethoxyiminomethyl and 2-(methoxyimino)ethyl.
It will be understood that when formula I compounds contain a chiral center, the compounds of the invention may exist in, and be isolated in, optically active or racemic form. The invention includes any optically active or racemic form of a compound of formula I which possesses pain-relieving properties. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by, resolution of a racemic form, by synthesis from optically active starting materials or by asymmetric synthesis. It will also be appreciated that certain compounds of formula I may exist as geometrical isomers. The invention includes any geometrical isomer of a compound of formula I which possesses pain-relieving properties.
It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms which possess the property of relieving pain.
It will further be understood that the present invention encompasses tautomers of the compounds of the formula (I).
Preferably A is optionally substituted: phenyl, naphthyl, thiadiazolyl, thienyl, pyridyl or pyrimidyl.
Preferably B is optionally substituted: pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl, or oxazolyl.
Most preferably A is optionally substituted: phenyl or thienyl.
Most preferably B is optionally substituted: pyridyl, phenyl, thienyl, pyridazinyl or thiazolyl.
In particular A is optionally substituted phenyl.
In particular B is optionally substituted: pyrid-2,5-diyl, pyridazin-3,6-diyl, phen-1,4-diyl or thien-2,5-diyl.
Most particularly B is optionally substituted pyridazin-3,6-diyl or pyrid-2,5-diyl.
Most preferably B is pyridazinyl.
Preferred optional substituents for ring carbon atoms in A, are halo, nitro, trifluoromethyl, cyano, amino, C1-6alkoxy, carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C1-4alkanoylamino, C1-6alkylS(O)p-, C1-4alkanesulphonamido, benzenesulphonamido, C1-16alkanoyl, C1-4alkoxyiminoC1-4alkyl and hydroxyiminoC1-4alkyl.
Preferably, when A is a 6-membered ring, A is unsubstituted or substituted in the 4-position relative to the xe2x80x94OR4 group.
Preferred optional substituents for ring carbon atoms of B are halo, trifluoromethyl, C1-4alkyl, amino, C1-4 alkylamino, diC1-4alkylamino, nitro, hydroxy, C1-6alkoxy and cyano.
Preferably A is unsubstituted or substituted by one substituent.
More preferably A is unsubstituted or substituted by bromo, methanesulphonyl, fluoro or chloro.
Most preferably A is unsubstituted or substituted by bromo or chloro.
Preferably B is unsubstituted or substituted by one substituent.
Most preferably B is unsubstituted.
Preferably R1 is carboxy, carbamoyl or tetrazolyl or R1 is of the formula xe2x80x94CONRaRa1 wherein Ra is hydrogen or C1-6alkyl and Ra1 is C1-6alkyl optionally substituted by hydroxy, C2-6alkenyl, 1-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, pyridylC1-3alkyl or R1 is of the formula xe2x80x94CONHSO2Rb wherein Rb is optionally substituted C1-6alkyl, phenyl or 5- or 6-membered heteroaryl.
In particular, R1 is carboxy, tetrazolyl or of the formula xe2x80x94CONRaRa1 wherein Ra is hydrogen and Ra1 is C1-6alkyl optionally substituted by hydroxy or pyridylmethyl, or R1 is of the formula xe2x80x94CONHSO2Rb wherein Rb is C1-6allyl (optionally substituted by hydroxy or fluoro), phenyl (optionally substituted by acetamido), isoxazolyl (optionally substituted by methyl) or 1,3,4-thiadiazolyl (optionally substituted by acetamido).
Most preferably R1 is carboxy, tetrazole or of the formula xe2x80x94CONHRa1 wherein Ra1 is pyridylmethyl or C1-4alkyl optionally substituted by hydroxy, or of the formula xe2x80x94CONHSO2Rb wherein Rb is C1-4 alkyl, 3,5-dimethylisoxazol-4-yl, or 5-acetamido-1,3,4-thiadiazol-2-yl.
In another aspect R1 is carboxy, carbamoyl or tetrazolyl or R1 is of the formula xe2x80x94CONRa Ra1 wherein Ra is hydrogen or C1-6alkyl and Ra1 is C1-6alkyl optionally substituted by hydroxy, C2-6alkenyl, 1-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, pyridylC1 3alkyl or R1 is of the formula xe2x80x94CONHSO2Rb wherein Rb is C1-6alkyl or phenyl.
Preferably R2 is hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, cyanomethyl, allyl or 3-propynyl.
More preferably R2 is hydrogen, methyl, ethyl or propyl.
Yet more preferably R2 is hydrogen or ethyl.
Most preferably R2 is ethyl.
Preferably R3 is hydrogen.
Preferably R4 is optionally substituted by halo, hydroxy, C1-4alkoxy, amino, carboxy, C1-4 alkylS(O)p-(p=0, 1 or 2), carbamoyl, trifluoromethyl, oxo or cyano.
More preferably R4 is optionally substituted by fluoro, chloro or bromo.
Most preferably R4 is optionally substituted by fluoro, trifluoromethyl, cyano or hydroxy.
Preferably R4 is C1-4alkyl, C3-6cycloalkyl or C3-6cycloalkylmethyl.
More preferably R4 is propyl, isobutyl, butyl, 2-ethylbutyl, 2(R)-methylbutyl, 2(S)-methylbutyl, 2,2,2-trifluoroethyl, cyclopentylmethyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.
Most preferably R4 is propyl, isobutyl, butyl, 2-ethylbutyl, cyclopentyl, cyclopropylmethyl or cyclopropyl:
A preferred class of compounds is that of the formula (I): 
wherein
R1 and R2 are as hereinabove defined, R4 is C1-4alkyl, C3-6cycloalkyl or C3-6 cycloalkylmethyl, R5 is hydrogen or as hereinabove defined for substituents for ring carbon atoms in A, and B is phenyl, thienyl, pyridazinyl, pyridyl, or thiazolyl.
It is to be understood that, insofar as certain of the compounds of formula (I) defined above may exist in optically active or racemic forms, by virtue of the compounds of the formula (I) containing an asymmetric carbon atom, the invention includes in its definition of active ingredient any such optically active or racemic form which possesses pain relieving properties. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, pain relieving properties may be evaluated using the standard laboratory techniques referred to hereinafter.
An in vivo hydrolysable ester of a compound of the formula (I) containing carboxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid, for example, a pharmaceutically acceptable ester formed with a (1-6C)alcohol such as methanol, ethanol, ethylene glycol, propanol or butanol, or with a phenol or benzyl alcohol such as phenol or benzyl alcohol or a substituted phenol or benzyl alcohol wherein the substituent is, for example, a halo (such as fluoro or chloro), (1-4C)alkyl (such as methyl) or (1-4C)alkoxy (such as ethoxy) group. The term also includes xcex1-acyloxyalkyl esters and related compounds which break down to give the parent hydroxy group. Examples of a-acyloxyalkyl esters include acetoxymethoxycarbonyl and 2,2-dimethylpropionyloxymethoxycarbonyl.
An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent alcohol. The term includes inorganic esters such as phosphate esters and a-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester break down to give the parent hydroxy group. Examples of xcex1-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
A suitable value for an in vivo hydrolysable amide of a compound of the formula I containing a carboxy group is, for example, a N-(1-6C)alkyl or N,N-di-(1-6C)alkyl amide such as N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.
A suitable pharmaceutically-acceptable salt of a compound of the formula (I) is, for example, an acid-addition salt of a compound of the formula (I) which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a compound of the formula (I) which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
In a further aspect the invention provides a process for preparing compounds of the formula (I) or pharmaceutically acceptable salts or in vivo hydrolysable amides or esters thereof, which comprises deprotecting a compound of the formula (III): 
wherein R6 is R1 or protected R1, R7 is R2 or protected R2 and, R3, R4, A and B are as hereinabove defmed, and any optional substituents are optionally protected and at least one protecting group is present;
and thereafter if necessary:
i) forming a pharmaceutically acceptable salt;
ii) forming an in vivo hydrolysable ester or amide;
iii) converting one optional substituent into another optional substituent.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods.
Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
A suitable protecting group for a hydroxy group is, for example, an arylmethyl group (especially benzyl), a tri-(1-4C)alkylsilyl group (especially trimethylsilyl or tert-butyldimethylsilyl), an aryldi-(1-4C)alkylsilyl group (especially dimethylphenylsilyl), a diaryl-(1-4C)alkylsilyl group (especially tert-butyldiphenylsilyl), a (1-4C)alkyl group (especially methyl), a (2-4C)alkenyl group (especially allyl), a (1-4C)alkoxymethyl group (especially methoxymethyl) or a tetrahydropyranyl group (especially tetrahydropyran-2-yl).
The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal. Alternatively a trialkylsilyl or an aryldialkylsilyl group such as a tert-butyldimethylsilyl or a dimethylphenylsilyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric, phosphoric or trifluoroacetic acid, or with an alkali metal or ammonium fluoride such as sodium fluoride or, preferably, tetrabutylammonium fluoride. Alternatively an alkyl group may be removed, for example, by treatment with an alkali metal (1-4C)alkylsulphide such as sodium thioethoxide or, for example, by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide or, for example, by treatment with a boron or aluminum trihalide such as boron tribromide. Alternatively a (1-4C)alkoxymethyl group or tetrahydropyranyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric or trifluoroacetic acid.
Alternatively a suitable protecting group for a hydroxy group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl) or an aroyl group (especially benzoyl). The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
A suitable protecting group for an amino, imino or alkylamino group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl), a (1-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl). The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl, alkoxycarbonyl or aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a (1-4C)alkyl group (especially methyl or ethyl) which may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide; or, for example, a tert-butyl group which may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid.
In another aspect the compounds of the formula (I) or (III) may be prepared by:
a) reducing a compound of the formula (IV) 
b) when B is an activated heterocycle and R7 is hydrogen or C1-6alkyl reacting a compound of the formula (V) with a compound of the formula (VI): xe2x80x83X0xe2x80x94Bxe2x80x94R6xe2x80x83xe2x80x83(VI)
c) reacting a compound of the formula (VII) with a compound of the formula (VIII): xe2x80x83R7xe2x80x94NHxe2x80x94Bxe2x80x94R6xe2x80x83xe2x80x83(VII)
d) converting X2 to R6 in a compound of the formula (IX): 
e)when R7 is other than hydrogen, reacting a compound of the formula R7X3 with a compound of the formula (X): 
f) reacting a compound of the formula (XI) with a compound of the formula (XII): xe2x80x83X4xe2x80x94NHxe2x80x94Bxe2x80x94R6xe2x80x83xe2x80x83(XII)
g) reacting a compound of the formula (XIII) with a compound of the formula (XIV): xe2x80x83X6xe2x80x94NHxe2x80x94Bxe2x80x94R6xe2x80x83xe2x80x83(XIV)
h) reacting a compound of the formula (XV) with a compound of the formula X7R4: 
wherein R3, R4, R7, R9, A and B are as hereinabove defined and X0 and X1 are leaving groups, X2 is a precursor of R7, X3 is a leaving group, X4 is a removable activating group, X5 is a leaving group, X6 is an activating group and X7 is a leaving group; and thereafter if necessary;
i) removing any protecting groups;
ii) forming a pharmaceutically acceptable salt;
iii) forming an in vivo hydrolysable ester or amide;
iv) converting an optional substituent into another optional substituent.
Particular values for leaving groups include halogen, for example, chloro, bromo and iodo, sulphonates, for example tosylate, p-bromobenzenesulphonate, p-nitrobenzenesulphonate, methanesulphonate and triflate or phosphoric esters such as diarylphosphoric ester.
Compounds of the formula (IV) can be reduced using agents such as sodium borohydride or sodium cyanoborohydride. The compounds of the formula (IV) may be prepared by reacting a compound of the formula (VII) with a compound of the formula (XV) 
wherein A, R3 and R4 are as hereinabove defined.
The reaction between compounds of the formulae (VI) and (XV) may be carried out under standard conditions known in the art for the formation an imine (Schiffs base), which can be reduced in situ. For example imine formation and reduction in situ may be carried out in an inert solvent such toluene or tetrahydrofuran, in the presence of a reducing agent such as sodium cyanoborohydride (NaCNBH3) under acidic conditions (Synthesis 135, 1975; Org. Prep. Proceed. Int. 11, 201, 1979).
Compounds of the formulae (V) and (VI) may be reacted together under standard conditions for example, in an aprotic solvent such as DMF in the presence of a weak base, in a temperature range of ambient to 180xc2x0 C. Suitable values for X0 include, halo, tosylate, mesylate and triflate. In particular X0 is chloro or bromo.
The compounds of the formulae (VII) and (VIII) may be reacted together under in an aprotic solvent such as DMF, in the presence of a base such as potassium carbonate or sodium hydride and in a temperature range of 0xc2x0 C. to 100xc2x0 C. Suitable values for X1 include halo, tosylate, mesylate and triflate. In particular X1 is bromo.
A precursor of R7 is a group that can be converted into R7.
Particular values for X2 include cyano, carbamoyl, alkoxycarbonyl, carboxy and activated carboxy groups such as acid chlorides and activated esters.
The cyano group may be converted into a tetrazole ring by reacting, for example, with ammonium or tin azide in an aprotic solvent such as DMF, in a temperature range of 100xc2x0 C. to 130xc2x0 C. For further information on tetrazole synthesis see S. J. Wittenberger and B. J Donner JOC, 1993, 58, 4139-4141; BE Huff et al, Tet. Lett, 1993, L, 8011-8014; and J. V. Duncia et al, JOC 1991, 56, 2395-2400.
Alkoxycarbonyl may be converted into a carboxy group by acid or base hydrolysis. For example, base hydrolysis may be carried out in an organic solvent such as methanol or THF in a temperature range of ambient to 100xc2x0 C., in the presence of sodium hydroxide or potassium hydroxide.
Acid hydrolysis may, for example, be carried out in neat formic acid or neat trifluoroacetic acid optionally in an inert organic solvent such as dichloromethane.
An alkoxycarbonyl or an activated carboxy group, such as an acid chloride or activated ester, or an acyl group such as an alkanoyl group may be converted to an amide group by reacting with the appropriate amine in an inert solvent such as DMF or dichloromethane, in a temperature range of 0xc2x0 C. to 150xc2x0 C., preferably around ambient temperature, in the presence of a base such as triethylamine.
The compounds of the formulae (X) and R7X3 may be reacted together in an aprotic solvent such as DMF in the presence of a base such as sodium carbonate or sodium hydride. Suitable values for X3 are halo, tosylate, mesylate and triflate, in particular halo such as iodo.
The reaction between compounds of the formulae (XI) and (XII) is conveniently carried out under mild conditions known for the Mitsunobu reaction, for example in the presence of di (C1-4alkyl)azocarboxylate and triphenylphosphine or 1111-(azodicarbonyl)dipiperidine and tributylphosphine (Tet. Lett. 34, 1993, 1639-1642) in an inert solvent such as toluene, benzene, tetrahydrofuran or diethylether, in particular toluene. Examples of removable activating groups are tert-butyloxycarbonyl and trifluoroacetyl.
Compounds of the formulae (XIII) and (XIV) are generally reacted together in the presence of a strong base such as sodium hydride, lithium diisopropylamine or LiN(SiMe3)2, in DMF or an etherial solvent such as ethyl ether or THF in a temperature range of xe2x88x9278xc2x0 C. to ambient temperature. Suitable values for X5 are halogen, for example, methanesulphonate or tosylate. Examples of activating groups for X6 include tert-butyloxycarbonyl, halogen and trifluoroacetyl.
The reaction between compounds of the formulae (XV) and X7R4 may be performed in an inert organic solvent such as acetone or DMF, in a temperature range of ambient temperature to 60xc2x0 C., in the present of a mild base. Suitable leaving groups include tosylate, mesylate, triflate and halo, or for example chloro or bromo. When X7 is bromo, (XV) and X7R4 may be reacted together for example, in DMF, at ambient temperature in the presence of a base such as potassium carbonate. Alternatively a phase transfer system could be used. X7 can be hydroxy which is activated in situ using the Mitsunobu reaction (O. Synthesis, 1981, 1.).
Compounds of the formula (XV) wherein R6 is R1 and R7 is R2 have pain-relieving properties in their own right.
Compounds of the formula (IV), (V), (VI), (IX), (X), (XI), (XIII) and (XV) can be prepared using processes for the formation of the lower linking group xe2x80x94OR4, similar to process h), from appropriate starting materials.
The compounds of the formula (IX) may be prepared using processes a), b), c), e), f), g) or h) from the appropriate starting material wherein R6 is replaced with X2.
The compounds of the formula (X) may be prepared by using any one of processes a), b), c), d), f), g) or h) from the appropriate starting materials wherein R7 is hydrogen.
The compounds of the formula (XII) can readily be prepared from compounds of the formula (VII).
The compounds of the formulae (VI), (VII), (XII) and (XIV) are generally known in the art or can be made by methods analogous to or similar to those used in the examples or those known in the art for related compounds. Certain compounds of the formula (VI), wherein X is chloro or bromo, can be prepared by converting an oxo group in the ring system into chloro or bromo by reacting the oxo ring system with a chlorinating agent, such as sulphonyl chloride, phosphorous trichloride, phosphorous pentachloride or P(O)Cl3 or brominating agent such as phosphorous tribromide or P(O)Br3, in an inert aprotic solvent.
It is also possible to synthesise certain intermediates and even protected compounds using primarily ring synthesis. Here, reference is made to the compendium xe2x80x98The Chemistry of Heterocyclic Compoundsxe2x80x99 E. C. Taylor and A. Weissberger (published by John Wiley and Sons) and xe2x80x98Comprehensive Heterocyclic Chemistryxe2x80x99, A. R Katritsky and C. W Rees (published by Pergamon Press).
Optional substituents may be converted into other optional substituents. For example an alkylthio group may be oxidised to an alkylsulphinyl or alkysulphonyl group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, or a bromo group replaced by an alkylthio group.
Various substituents may be introduced into compounds of the formulae (I) and (III) and intermediates in the preparation of compounds of the formulae (I) and (III), when appropriate, using standard methods known in the art. For example, an acyl group or alkyl group may be introduced into an activated benzene ring using Friedel-Crafts reactions, a formyl group by formylation with titanium tetrachloride and dichloromethyl ethyl ether, a nitro group by nitration with concentrated nitric acid concentrated sulphuric acid and bromination with bromine or tetra(n-butyl)ammonium tribromide.
It will be appreciated that, in certain steps in the reaction sequence to compounds of the formula (I), it will be necessary to protect certain functional groups in intermediates in order to prevent side reactions. Deprotection may be carried out at a convenient stage in the reaction sequence once protection is no longer required.
As stated hereinbefore compounds of the formula (I) are antagonists of the pain enhancing effects of E-type prostaglandins and of value in the relief of mild to moderate pain which, for example, accompanies inflammatory conditions such as rheumatoid arthritis and osteoarthritis. Certain properties of the compounds may be demonstrated using the test procedures set out below:
(a) an in vitro guinea pig ileum assay which assesses the inhibitory properties of a test compound against PGE2-induced contractions of the ileum; ileum was immersed in oxygenated Krebs solution containing indomethacin (4 xcexcg/ml) and atropine (1 xcexcM) and which was maintained at 37xc2x0 C.; the ileum was subject to a tension of 1 g; a control dose response curve for PGE2-induced contraction of the ileum was obtained; test compound (dissolved in dimethylsulphoxide) was added to the Krebs solution and a dose response curve for the PGE2-induced contraction of the ileum in the presence of the test compound was obtained; the pA2 value for the test compound was calculated;
(b) an in-vivo assay in mice which assesses the inhibitory properties of a test compound against abdominal constriction response induced by the intraperitoneal administration of a noxious agent such as dilute acetic acid or phenylbenzoquinone (hereinafter PBQ) using the procedure disclosed in European Patent Application No. 0218077.
Although the pharmacological properties of the compounds of the formula I vary with structural change as expected, in general activity possessed by compounds of the formula I may be demonstrated at the following concentrations or doses in one or more of the above-mentioned Tests (a) and (b):
Test (a):xe2x80x94pA2 greater than 5.3;
Test (b):xe2x80x94ED30 in the range, for example, 0.01-100 mg/kg orally.
No overt toxicity or other untoward effects were noted in Test (b) when compounds of the formula I are administered at several multiples of their minimum inhibitory dose.
Prostaglandin receptors and in particular receptors for PGE2 have been tentatively characterised by Kennedy et al. (Advances in Prostaglandin, Thromboxane and Leukotriene Research, 1983, 11, 327). The known PGE2 antagonist SC-19220 blocks the effect of PGE2 on some tissues such as guinea pig ileum or dog fundus but not on other tissues such as the cat trachea or chick ileum. Those tissues which did possess SC-19220 sensitive mediated effects were said to possess EP1 receptors. Based on this compounds of the present invention, possessing activity in Test (a), are EP1 antagonists.
According to a further feature of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) or an in-vivo hydrolysable ester thereof or an amide thereof, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel, spray or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository or rectal spray; for administration by inhalation, for example as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients.
The amount of active ingredient (that is a compound of the formula (I) or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
According to a further feature of the invention there is provided a compound of the formula (I) or an in vivo hydrolysable ester or amide or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the animal (including human) body by therapy.
According to a further feature of the invention there is provided the use of a compound of the formula I, or an in vivo hydrolysable ester or amide or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use in the relief of pain in the animal (including human) body.
According to a further feature of the invention there is provided a method for the relief of pain in the animal (including human) body in need of such treatment which comprises administering to said body an effective amount of a compound of the formula I, or an in-vivo hydrolysable ester or amide or a pharmaceutically-acceptable salt thereof.
As mentioned above, a compound of the formula (I) is useful in treating the pain which, for example, accompanies inflammatory conditions such as rheumatoid arthritis and osteoarthritis. In using a compound of the formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.05 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg to 25 mg per kg body weight will be used.
Although the compounds of the formula (I) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to antagonise the effects of PGE2 at the EP1 receptor, based on test a). Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
By virtue of their ability to relieve pain, the compounds of the formula I are of value in the treatment of certain inflammatory and non-inflammatory diseases which are currently treated with a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug (NSAID) such as indomethacin, ketorolac, acetylsalicyclic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of a compound of the formula I with a NSAID can result in a reduction of the quantity of the latter agent needed to produce a therapeutic effect. Thereby the likelihood of adverse side-effects from the NSAID such as gastrointestinal effects are reduced. Thus according to a further feature of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or an in-vivo hydrolysable ester or amide or pharmaceutically-acceptable salt thereof, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent, and a pharmaceutically-acceptable diluent or carrier.
The compounds of the invention may also be used with other anti-inflammatory agents such as an inhibitor of the enzyme 5-lipoxygenase (such as those disclosed in European Patent Applications Nos. 0351194, 0375368, 0375404, 0375452, 0375457, 0381375, 0385662, 0385663, 0385679, 0385680).
The compounds of the formula (I) may also be used in the treatment of conditions such as rheumatoid arthritis in combination with antiarthritic agents such as gold, methotrexate, steroids and penicillinamine, and in conditions such as osteoarthritis in combination with steroids.
The compounds of the present invention may also be administered in degradative diseases, for example osteoarthritis, with chondroprotective, anti-degradative and/or reparative agents such as Diacerhein, hyaluronic acid formulations such as Hyalan, Rumalon, Arteparon and glucosamine salts such as Antril.
The compositions of the invention may in addition contain one or more other therapeutic or prophylactic agents known to be of value for the treatment of pain. Thus for example, a known opiate pain-killer (such as dextropropoxyphene, dehydrocodeine or codeine) or an antagonist of other pain or inflammation mediators, such as bradykinin, takykinin and calcitonin gene related peptides (CGRP), or an alpha2adrenoceptor agonist, a GABAB receptor agonist, a calcium channel blocker, a sodium channel blocker, a CCKB receptor antagonist, a neurokinin antagonist or an antagonist and modulator of the action of glutamate at the NMDA receptor may usefully also be present in a pharmaceutical composition of the invention.
The compounds of the present invention may also be administered in bone diseases such as osteoporosis with calcitonin and bisphosphonates.
The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:
(i) evaporations were carried out by rotary evaporations in vacuo and work-up procedures were carried out after removal or residual solids by filtration;
(ii) yields are given for illustration only and are not necessarily the maximum attainable;
(iii) the end-products of the formula I have satisfactory microanalysis and their structures were generally confirmed by NMR and mass spectral techniques;
(iv) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula I were determined after recrystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture;
(v) the following abbreviations have been used:
DMF N,N-dimethylformamide;
THF tetrahydrofuran
DMSO dimethylsulphoxide
TLC thin layer chromatography
MPLC medium pressure liquid chromatography